MHY2233 Attenuates Replicative Cellular Senescence in Human Endothelial Progenitor Cells via SIRT1 Signaling.

Shreekrishna Lamichane,Li Dehua,Woong Bi Jang,Da Yeon Kim,Seungtaek Ji,Songhwa Kang,Yeon-Ju Kim,Dong Hyung Lee,Babita Dahal Lamichane,Hae Young Chung,Na Kyung Lee,Sang Hong Baek,Ha Jong Seong,Hyung Ryong Moon,Ji Hye Park,Sang-Mo Kwon,Jisoo Yun

doi:10.1155/2019/6492029

Abstract

Cardiovascular diseases (CVDs) are a major cause of death worldwide. Due to the prevalence of many side effects and incomplete recovery from pharmacotherapies, stem cell therapy is being targeted for the treatment of CVDs. Among the different types of stem cells, endothelial progenitor cells (EPCs) have great potential. However, cellular replicative senescence decreases the proliferation, migration, and overall function of EPCs. Sirtuin 1 (SIRT1) has been mainly studied in the mammalian aging process. MHY2233 is a potent synthetic SIRT1 activator and a novel antiaging compound. We found that MHY2233 increased the expression of SIRT1, and its deacetylase activity thereby decreased expression of the cellular senescence biomarkers, p53, p16, and p21. In addition, MHY2233 decreased senescence-associated beta-galactosidase- (SA-β-gal-) positive cells and senescence-associated secretory phenotypes (SASPs), such as the secretion of interleukin- (IL-) 6, IL-8, IL-1α, and IL-1β. MHY2233 treatment protected senescent EPCs from oxidative stress by decreasing cellular reactive oxygen species (ROS) levels, thus enhancing cell survival and function. The angiogenesis, proliferation, and migration of senescent EPCs were enhanced by MHY2233 treatment. Thus, MHY2233 reduces replicative and oxidative stress-induced senescence in EPCs. Therefore, this novel antiaging compound MHY2233 might be considered a potent therapeutic agent for the treatment of age-associated CVDs.

Highlights

Cardiovascular diseases (CVDs) are the leading cause of death throughout the world [1,2,3]
Isolated Mononuclear cells (MNCs) were seeded in 1% gelatin- (SigmaAldrich, USA) coated culture plates and cultured in endothelium growth medium-2 (EGM-2) (Lonza, USA): endothelium basal medium-2 (EBM-2) containing 5% fetal bovine serum (FBS), 1% penicillin-streptomycin (PS), human vascular endothelial growth factor (VEGF), human basic fibroblast growth factor (b-FGF), human insulin-like growth factor-1 (IGF-1), human epidermal growth factor (EGF), ascorbic acid, and GA-1000
The mRNA level of Sirtuin 1 (SIRT1) was found to be decreased markedly, but the mRNA level of p53, p21, and p16 was significantly increased in senescent endothelial progenitor cells (EPCs) when compared with that of young EPCs (Supplementary Figure S1)

Summary

Introduction

Cardiovascular diseases (CVDs) are the leading cause of death throughout the world [1,2,3]. Among various CVDs, tissue ischemia associated with stroke and coronary heart disease represents the majority [2]. Different types of stem cells that are utilized for the treatment of ischemic heart diseases include mesenchymal stem cells (MSCs), adipose tissue-derived stem cells (Ad-MSCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), endothelial progenitor cells (EPCs), and cardiac progenitor cells (CPCs) [4]. Circulating EPCs maintain endothelial integrity and neovascular functions; they are candidates for cell therapy in CVDs [1, 5]. EPCs have a high capacity to migrate, proliferate, and differentiate into mature endothelial cells (ECs) [6]. Stem cells lose their self-renewal capacity to proliferate, differentiate, migrate, and restitute the original function of damaged cells [5]. Bone marrow-derived EPCs from young rats improved angiogenesis in impaired myocardium more than those from the aged rats [7]

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